Abstract 17806: Protective Roles of Small GTP-binding Protein GDP Dissociation Stimulator Against Angiotensin II-induced Thoracic Aortic Aneurysm Formation And Rupture in Mice -A Possible Novel Therapeutic Target

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Background: Statins reduce the incidence and development of thoracic aortic aneurysm (TAA) and rupture. We have previously identified that small GTP-binding protein GDP dissociation stimulator (SmgGDS) is a crucial mediator of the pleiotropic effects of statins.

Methods and Results: To examine the role of SmgGDS in TAA formation, Apoe-/- and Apoe-/-SmgGDS+/- (DKO) mice were infused with angiotensin II (AngII, 1,000 ng/min/kg) for 4 weeks. There was no significant difference in blood pressure between the 2 genotypes in response to the AngII treatment. However, 33% of DKO mice (n=15) died suddenly due to TAA rupture, whereas there was no TAA rupture in Apoe-/- mice (n=13, P<0.05). Histological analysis of DKO mice showed dissections of major thoracic aorta in the early phase of AngII infusion (day 3~5) and more severe elastin degradation compared with Apoe-/- mice (P<0.05, n=5 each). We performed ultrasound imaging every week to follow the serial changes in aortic diameters. Diameter of the ascending aorta was progressively increased in DKO mice compared with Apoe-/- mice (1.64±0.06 vs. 1.43±0.05 mm at 4 weeks, P<0.05), whereas that of the abdominal aorta was comparable between the 2 genotypes. Western blotting demonstrated that AngII-induced activations of JNK, ERK, and Rac1 were significantly higher in the thoracic aorta of DKO mice compared with that of Apoe-/- mice (P<0.05, n=6 each). For mechanistic analyses, we primary cultured aortic smooth muscle cells (AoSMCs) from the 2 genotypes. After AngII (100 nM) treatment for 24 hours, DKO AoSMCs showed significantly increased JNK activity, Rac1 expression, and oxidative stress levels compared with Apoe-/- AoSMCs (P<0.01, n=6 each). Interestingly, AngII-induced Nrf2 upregulation was significantly less in DKO AoSMCs compared with Apoe-/- AoSMCs (P<0.01, n=6). Moreover, MMP activities were significantly increased in DKO AoSMCs compared with Apoe-/- AoSMCs. Finally, expression of FBN1 was significantly reduced in DKO AoSMCs compared with Apoe-/- AoSMCs (n=6, P<0.05). Similar tendency was noted in AoSMCs from TAA patients (n=6) compared with those from controls (n=4) (P<0.05).

Conclusions: These results suggest that SmgGDS is a novel therapeutic target for the prevention and treatment of TAA.

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